Immunological adjuvant compounds compositions and methods of use thereof

Abstract

The present invention provides novel compounds that function as immunological adjuvants when co-administered with antigens, including, antigens used as vaccines for any disease or condition amenable to vaccination. The invention also provides adjuvant formulations comprising the novel compounds of the invention and methods for immunizing humans and non-human animals.

What is claimed is:  
     
       1. A compound of the formula I:                    
       wherein 
       R 1  is selected from the group consisting of  
       (a) —C(O)—;  
       (b) —C(O)—C 1-14  alkylene-C(O)— or —C(O)—C 1-14  alkenylene-C(O)—, wherein the C 1-14  alkylene or C 1-14  alkenylene is optionally substituted with hydroxy, C 1-6  alkoxy, C 1-6  alkylenedioxy, carboxy, C 1-6  alkoxycarbonyl, C 1-6  carbamoyl, C 1-6  acylamino, C 1-6  alkylamino, or (aryl)C 1-6  alkyl, wherein said aryl moiety of said (aryl)C 1-6  alkyl is optionally substituted with C 1-6  alkyl, C 1-6  alkoxy, C 1-6  alkylamino, (C 1-6  alkoxy)C 1-6  alkylamino, (C 1-6  alkylamino)C 1-6  alkoxy, —O—C 1-6  alkylene-NH—C 1-6 alkylene-O—C 1-6  alkyl, —O—C 1-6  alkylene-NH—C(O)—C 1-6  alkylene-C(O)OH, or —O—C 1-6  alkylene-NH—C(O)—C 1-6  alkylene-C(O)—C 1-6  alkyl;  
       (c) C 2  to C 15  straight or branched chain alkyl optionally substituted with hydroxy or alkoxy; and  
       (d) —C(O)—C 6-12  arylene-C(O)— wherein said arylene is optionally substituted with C 1-6  alkyl, hydroxy, C 1-6  alkoxy, halogen, nitro or amino;  
       a and b are independently an integer from 0 to about 4;  
       d and e are independently an integer from 1 to about 6;  
       d′ and e′ are independently an integer from 0 to about 2;  
       X 1  and Y 1  are independently selected from the group consisting of a null, oxygen, —NH—, —N(C(O)C 1-4  alkyl)-, and —N(C 1-4  alkyl)-;  
       G 1 , G 2 , G 3 , and G 4  are independently selected from the group consisting of oxygen, methylene, —NH—, —N(C 1-4  alkyl)-, —N[C(O)—C 1-4  alkyl]-, —NH—C(O)—, —NH— SO 2 —, —C(O)—O—, —C(O)—NH—, —O—C(O)—, —O—C(O)—NH—, —O—C(O)—O—, —NH—C(O)—NH—, —C(O)NH—, C(O)N(C 1-4  alkyl), and —S(O) n —, where n is 0, 1, or 2;  
       R 2 , R 3 , R 4 , R 5 , R 6 , and R 7  are independently selected from the group consisting of:  
       (a) C 1  to C 20  straight chain or branched chain alkyl which is optionally substituted with halo, oxo, hydroxy or alkoxy;  
       (b) C 2  to C 20  straight chain or branched chain alkenyl, alkynyl, or dialkenyl which is optionally substituted with halo, oxo, hydroxy or alkoxy; and                    
        wherein  
       R 8  is C 1-6  straight or branched chain alkyl or C 2-6  straight or branched chain alkenyl, alkynyl, or dialkenyl;  
       G 5  is selected from the group consisting of oxygen, methylene, arylene, —NH—, —N(C 1-4  alkyl)-, —N(C(O)—C 1-4  alkyl)-, —NH—C(O)—, —NH—SO 2 —, —C(O)—O—, —C(O)—NH—, —O—C(O)—, —O—C(O)—NH—, —O—C(O)—O—, —NH—C(O)—NH—, and —S(O) n —, where n is 0, 1, or 2;  
       R 9  and R 10  are independently selected from the group consisting of  
       (i) C 1  to C 20  straight chain or branched chain alkyl which is optionally substituted with halo, oxo, hydroxy or alkoxy; and  
       (ii) C 2  to C 20  straight chain or branched chain alkenyl, alkynyl, or dialkenyl which is optionally substituted with halo, oxo, hydroxy or alkoxy;  
        or any one or two of G 1 R 2 , G 2 R 4 , G 3 R 5 , and G 4 R 7  may together be a hydrogen atom or hydroxyl;  
       or a pharmaceutically acceptable salt thereof. 
     
     
       2. The compound according to  claim 1 , wherein each of a and b is 2. 
     
     
       3. The compound according to  claim 1 , wherein each of X 1  and Y 1  is NH. 
     
     
       4. The compound according to  claim 1 , wherein each of d and e is 1 or 2. 
     
     
       5. The compound according to  claim 1 , wherein each of d′ and e′ is 0, 1, or 2. 
     
     
       6. The compound according to  claim 1 , wherein each of d and e is 1, and each of d′ and e′ is 0. 
     
     
       7. The compound according to  claim 1 , wherein each of d and e is 1, and each of d′ and e′ is 1 or 2. 
     
     
       8. The compound according to  claim 1 , wherein R 1  is —C(O)— or —C(O)—C 1-14  alkylene-C(O)—, wherein the C 1-14  alkylene is optionally substituted with one or two substituents selected from the group consisting of hydroxy, C 1-6  alkoxy, C 1-6  alkylenedioxy, C 1-6  alkylamino, or (aryl)C 1-6  alkyl, wherein said aryl moiety of said (aryl)C 1-6  alkyl is optionally substituted with C 1-6  alkyl, C 1-6 alkoxy, C 1-6  alkylamino, (C 1-6  alkoxy)C 1-6  alkylamino, (C 1-6  alkylamino)C 1-6  alkoxy, —O—C 1-6  alkylene-NH—C 1-6 alkylene-O—C 1-6  alkyl, —O—C 1-6  alkylene-NH—C(O)—C 1-6  alkylene-C(O)OH, or —O—C 1-6  alkylene-NH—C(O)—C 1-6  alkylene-C(O)—C 1-6  alkyl. 
     
     
       9. The compound according to  claim 1 , wherein G 1 , G 2 , G 3 , and G 4  are each independently selected from the group consisting of —NH—C(O)— and —O—C(O)—. 
     
     
       10. The compound according to  claim 1 , wherein at least two of R 2 -R 7 , R 9 , and R 10  are C 6-20  straight or branched chain alkyl, alkenyl, or dialkenyl, any of which groups may be optionally substituted with one or two substituents selected from the group consisting of halo, oxo, hydroxy, and alkoxy. 
     
     
       11. The compound according to  claim 1 , wherein at least four of R 2 -R 7 , R 9 , and R 10  are C 6-20  straight or branched chain alkyl, alkenyl, or dialkenyl, any of which groups may be optionally substituted with one or two substituents selected from the group consisting of halo, oxo, hydroxy, and alkoxy. 
     
     
       12. The compound according to  claim 1 , wherein at least six of R 2 -R 7 , R 9 , and R 10  are C 6-20  straight or branched chain alkyl, alkenyl, or dialkenyl, any of which groups may be optionally substituted with one or two substituents selected from the group consisting of halo, oxo, hydroxy, and alkoxy. 
     
     
       13. The compound according to  claim 1 , wherein at least two of R 2 -R 7 , R 9 , and R 10  are C 8-15  straight or branched chain alkyl, alkenyl, or dialkenyl, any of which groups may be optionally substituted with one or two substituents selected from the group consisting of halo, oxo, hydroxy, and alkoxy. 
     
     
       14. The compound according to  claim 1 , wherein at least four of R 2 -R 7 , R 9 , and R 10  are C 8-15  straight or branched chain alkyl, alkenyl, or dialkenyl, any of which groups may be optionally substituted with one or two substituents selected from the group consisting of halo, oxo, hydroxy, and alkoxy. 
     
     
       15. The compound according to  claim 1 , wherein at least six of R 2 -R 7 , R 9 , and R 10  are C 8-15  straight or branched chain alkyl, alkenyl, or dialkenyl, any of which groups may be optionally substituted with one or two substituents selected from the group consisting of halo, oxo, hydroxy, and alkoxy. 
     
     
       16. An immunological adjuvant formulation comprising a compound of the formula I:                    
       wherein 
       R 1  is selected from the group consisting of  
       (a) —C(O)—;  
       (b) —C(O)—C 1-14  alkylene-C(O)— or —C(O)—C 1-14  alkenylene-C(O)—, wherein the C 1-14  alkylene or C 1-14  alkenylene is optionally substituted with hydroxy, C 1-6  alkoxy, C 1-6  alkylenedioxy, carboxy, C 1-6  alkoxycarbonyl, C 1-6 carbamoyl, C 1-6  acylamino, C 1-6  alkylamino, or (aryl)C 1-6  alkyl, wherein said aryl moiety of said (aryl)C 1-6  alkyl is optionally substituted with C 1-6  alkyl, C 1-6  alkoxy, C 1-6  alkylamino, (C 1-6  alkoxy)C 1-6  alkylamino, (C 1-6  alkylamino)C 1-6  alkoxy, —O—C 1-6  alkylene-NH—C 1-6 alkylene-O—C 1-6  alkyl, —O—C 1-6 alkylene-NH—C(O)—C 1-6  alkylene-C(O)OH, or —O—C 1-6  alkylene-NH—C(O)—C 1-6  alkylene-C(O)—C 1-6  alkyl;  
       (c) C 2  to C 15  straight or branched chain alkyl optionally substituted with hydroxy or alkoxy; and  
       (d) —C(O)—C 6-12  arylene-C(O)— wherein said arylene is optionally substituted with C 1-6  alkyl, hydroxy, C 1-6  alkoxy, halogen, nitro or amino;  
       a and b are independently an integer from 0 to about 4;  
       d and e are independently an integer from 1 to about 6;  
       d′ and e′ are independently an integer from 0 to about 2;  
       X 1  and Y 1  are independently selected from the group consisting of a null, oxygen, —NH—, —N(C(O)C 1-4  alkyl)-, and —N(C 1-4  alkyl)-;  
       G 1 , G 2 , G 3 , and G 4  are independently selected from the group consisting of oxygen, methylene, —NH—, —N(C 1-4  alkyl)-, —N[C(O)—C 1-4  alkyl]-, —NH—C(O)—, —NH—SO 2 —, —C(O)—O—, —C(O)—NH—, —O—C(O)—, —O—C(O)—NH—, —O—C(O)—O—, —NH—C(O)—NH—, and —C(O)NH—, C(O)N(C 1-4  alkyl), —S(O) n —, where n is 0, 1, or 2;  
       R 2 , R 3 , R 4 , R 5 , R 6 , and R 7  are independently selected from the group consisting of:  
       (a) C 1  to C 20  straight chain or branched chain alkyl which is optionally substituted with halo, oxo, hydroxy or alkoxy;  
       (b) C 2  to C 20  straight chain or branched chain alkenyl, alkynyl, or dialkenyl which is optionally substituted with halo, oxo, hydroxy or alkoxy; and                    
        wherein  
       R 8  is C 1-6  straight or branched chain alkyl or C 2-6  straight or branched chain alkenyl, alkynyl, or dialkenyl;  
       G 5  is selected from the group consisting of oxygen, methylene, arylene, —NH—, —N(C 1-4  alkyl)-, —N(C(O)—C 1-4  alkyl)-, —NH—C(O)—, —NH—SO 2 —, —C(O)—O—, —C(O)—NH—, —O—C(O)—, —O—C(O)—NH—, —O—C(O)—O—, —NH—C(O)—NH—, and —S(O) n —, where n is 0, 1, or 2;  
       R 9  and R 10  are independently selected from the group consisting of  
       (i) C 1  to C 20  straight chain or branched chain alkyl which is optionally substituted with halo, oxo, hydroxy or alkoxy; and  
       (ii) C 2  to C 20  straight chain or branched chain alkenyl, alkynyl, or dialkenyl which is optionally substituted with halo, oxo, hydroxy or alkoxy;  
        or any one or two of G 1 R 2 , G 2 R 4 , G 3 R 5 , and G 4 R 7  may together be a hydrogen atom or hydroxyl;  
       or a pharmaceutically acceptable salt thereof; and  
       a pharmaceutically acceptable carrier, diluent or excipient.